Decreased function of insulin-producing ?-cells in the pancreas is a key contributor to the etiology of type 2 diabetes. Blunted ?-cell secretion is one f the earliest features of the disease, that precedes the onset of overt hyperglycemia. Thus, it is critical to identify factors that regulate normal ?-cell secretory responses and identify their mechanisms of action, so that therapeutic strategies can be targeted toward early intervention during ?-cell failure. Neurotrophins are soluble peptide growth factors that have been best-studied as essential regulators of neuronal development and synaptic transmission in the vertebrate nervous system. Despite the wide-spread expression of neurotrophins and their Trk receptor tyrosine kinases in non-neuronal tissues, including the pancreas, little has been done to investigate their in vivo functions outside of the nervous system. Employing genetic mouse models, we uncovered an endogenous role for the classical neurotrophin, Nerve Growth Factor (NGF) in glucose-stimulated insulin secretion. Thus, the overall goal of this proposal is to define this new role for neurotrophin signaling in ?-cell function, and to elucidate the underlying molecular mechanisms. Based on preliminary findings, we hypothesize that NGF is a vascular-derived signal that acts on ?-cell-localized TrkA receptors to acutely augment glucose-stimulated insulin secretion. The goal of Aim 1 is to define the essential roles of NGF and TrkA in adult ?-cell function, by assessing glucose homeostasis and insulin secretion in mice in which NGF and TrkA receptors have been inducibly deleted from vascular and ?-cells, respectively. In Aim 2, we will identify the molecular mechanisms by which TrkA signaling in ?-cells influences insulin secretion. Preliminary results suggest that TrkA-mediated vesicular trafficking and actin cytoskeletal mechanisms are responsible for mobilizing insulin granules to the ?-cell plasma membrane. Thus, we will elucidate the role of Trk receptor endocytosis and endosomal signaling in glucose-stimulated changes in actin and insulin granule exocytosis, employing biochemical, live-imaging and ultra- structural assays. The significance of our study is that it is the first to address the essential functions of neurotrophins, classically studied as neuronal factors, in the endocrine system. Our findings have the potential to inform a new line of research in current translational efforts to treat metabolic disorders.